Nicotinic acetylcholine receptors (nAChRs), which are the ligand gated ion channels at which nicotine acts, play an important role in drug abuse and may be central to developing rational approaches for substance abuse treatments. Regional cerebral metabolic rates for glucose were assayed using the 2-deoxy-D-[1-[C-14]C]glucose technique to elucidate the effect of nicotinic antagonist, mecamylamine, on brain function in rats receiving chronic nicotine. Although mecamylamine reversed the increase in cerebral glucose metabolism observed in animals that received nicotine, it did not produce withdrawal signs, supporting to the view that mecamylamine in combination with nicotine, is efficacious in treating nicotine dependence. Studies with [H-3]-cytisine, [H-3]-epibatidine and two novel radioactive ligands developed in our lab, [I-125]-5-I-A-85380 (5-iodo-3-(2(S)-azetidinylmethoxy)pyridine and [F-18]-2-F-A-85380 indicate that 5-I-A-85380 and 2-F-A-85380 binds specifically and selectively to the alpha4beta2 subtype of nAChRs. The results of saturation, kinetic and competition studies performed with [H-3]-epibatidine and [I-125]-5-I-A-85380 in brains of mice lacking beta2 subunits of nAChRs ("knockout" mice) suggest that the high affinity population of [H-3]-epibatidine binding sites characterizes the interaction of these ligands with alpha4beta2 nAChRs subtype.